The ability to non-invasively image molecular targets in vivo using magnetic resonance imaging (MRI) represents a major advance in the field of diagnostic imaging. In this project, we propose to develop novel MRI probes which will allow for imaging of the expression of matrix metalloproteinases (MMPs) in vivo. MMPs are over expressed in many pathological process, including cancer, cardiovascular, inflammatory, and immune diseases. In the central nervous system, MMPs are known to be over expressed in high-grade gliomas and multiple sclerosis (MS). The ability to image the levels of MMPs in vivo will have profound ramifications on cur understanding of these disease process, their response to treatment, and our ability to develop new, more effective pharmacological agents. In Phase I (R21) of this project, we will develop the novel MRI probes and evaluate them on a rat CS glioma model. This phase has three specific aims: Specific Aim #1: Development of a MMP-2 activated permeability modulator. Specific Aim #2: Development of a MMP-2 activated organometallic-based probe. Specific Aim #3: In vivo imaging of MMP-2 expression in a CS glioma model. In Phase II (R33) of this project, we will extend this new technology to study other pathological processes, as well as evaluate the ability of our vascular permeability probe to improve local delivery of pharmacological agents. This phase has three specific aims: Specific Aim #1: In vivo imaging of MMP-2 expression in human tumor xenografts. Specific Aim #2: In vivo imaging of MMP-9 expression in a rat EAE model of MS. Specific Aim #3: Evaluation of the ability of vascular permeability modulator to improve the therapeutic efficacy of pharmacological agents.